Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, University of Cape Town, Rondebosch 7701, South Africa.
J Med Chem. 2020 Nov 12;63(21):13013-13030. doi: 10.1021/acs.jmedchem.0c01411. Epub 2020 Oct 25.
A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite . Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, cytotoxicity, and cardiotoxicity and were addressed through structure-activity and structure-property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound showed good exposure in mice combined with good activity against the malaria parasite, which translated into efficacy in the NOD- (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
从高通量表型筛选针对人类疟原虫的文库中鉴定出一系列 2,4-二取代的咪唑并吡啶。这些命中化合物在无性血阶段具有中等活性。在进行先导化合物优化的过程中，发现了一些问题，例如对多药耐药 K1 株的交叉耐药性、细胞毒性和心脏毒性，并通过构效关系和结构性质关系研究解决了这些问题。对于具有理想活性、对细胞毒性有选择性窗口和良好的微粒体代谢稳定性的化合物，在小鼠中评估了药代动力学性质。先导化合物 显示出良好的小鼠暴露量，同时对疟原虫具有良好的活性，这转化为 NOD-（NSG）小鼠模型中的疗效。初步的机制研究表明抑制亚铁血红素形成是一种作用模式。
